Selective glucocorticoid receptor translational isoforms reveal glucocorticoid-induced apoptotic transcriptomes
Open Access
- 10 January 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 4 (1), e453
- https://doi.org/10.1038/cddis.2012.193
Abstract
Induction of T-cell apoptosis contributes to the anti-inflammatory and antineoplastic benefits of glucocorticoids. The glucocorticoid receptor (GR) translational isoforms have distinct proapoptotic activities in osteosarcoma cells. Here we determined whether GR isoforms selectively induce apoptosis in Jurkat T lymphoblastic leukemia cells. Jurkat cells stably expressing individual GR isoforms were generated and treated with vehicle or dexamethasone (DEX). DEX induced apoptosis in cells expressing the GR-A, -B, or -C, but not the GR-D, isoform. cDNA microarray analyses of cells sensitive (GR-C3) and insensitive (GR-D3) to DEX revealed glucocorticoid-induced proapoptotic transcriptomes. Genes that were regulated by the proapoptotic GR-C3, but not by the GR-D3, isoform likely contributed to glucocorticoid-induced apoptosis. The identified genes include those that are directly involved in apoptosis and those that facilitate cell killing. Chromatin immunoprecipitation assays demonstrated that distinct chromatin modification abilities may underlie the distinct functions of GR isoforms. Interestingly, all GR isoforms, including the GR-D3 isoform, suppressed mitogen-stimulated cytokines. Furthermore, the GR-C isoforms were selectively upregulated in mitogen-activated primary T cells and DEX treatment induced GR-C target genes in activated T cells. Cell-specific expressions and functions of GR isoforms may help to explain the tissue- and individual-selective actions of glucocorticoids and may provide a basis for developing improved glucocorticoids.Keywords
This publication has 53 references indexed in Scilit:
- Glucocorticoid Receptor α Isoform-Selective Regulation of Antiapoptotic Genes in Osteosarcoma Cells: A New Mechanism for Glucocorticoid ResistanceMolecular Endocrinology, 2011
- The Human Glucocorticoid Receptor as an RNA-Binding Protein: Global Analysis of Glucocorticoid Receptor-Associated Transcripts and Identification of a Target RNA MotifPublished by The American Association of Immunologists ,2011
- Glucocorticoids Modulate MicroRNA Expression and Processing during Lymphocyte ApoptosisJournal of Biological Chemistry, 2010
- lumi: a pipeline for processing Illumina microarrayBioinformatics, 2008
- Model-based variance-stabilizing transformation for Illumina microarray dataNucleic Acids Research, 2008
- Gene expression profiling of leukemic cells and primary thymocytes predicts a signature for apoptotic sensitivity to glucocorticoidsCancer Cell International, 2007
- Selective Regulation of Bone Cell Apoptosis by Translational Isoforms of the Glucocorticoid ReceptorMolecular and Cellular Biology, 2007
- Transcripts Targeted by the MicroRNA-16 Family Cooperatively Regulate Cell Cycle ProgressionMolecular and Cellular Biology, 2007
- Regulation of differential pro- and anti-apoptotic signaling by glucocorticoidsApoptosis, 2006
- p38‐MAP kinase activation followed by BIM induction is essential for glucocorticoid‐induced apoptosis in lymphoblastic leukemia cellsFEBS Letters, 2006